The ruthenium nitric oxide donor, [Ru(HEDTA)NO], inhibits acute nociception in mice by modulating oxidative stress, cytokine production and activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway.

Nitric oxide plays an important role in various biological processes including antinociception. The control of its local concentration is crucial for obtaining the desired effect and can be achieved with exogenous nitric oxide-carriers such as ruthenium complexes. Therefore, we evaluated the analgesic effect and mechanism of action of the ruthenium nitric oxide donor [Ru(HEDTA)NO] focusing on the role of cytokines, oxidative stress and activation of the cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway. It was observed that [Ru(HEDTA)NO] inhibited in a dose-dependent (1-10 mg/kg) manner the acetic acid-induced writhing response. At the dose of 1 mg/kg, [Ru(HEDTA)NO] inhibited the phenyl-p-benzoquinone-induced writhing response, and formalin- and complete Freund's adjuvant-induced licking and flinching responses. Systemic and local treatments with [Ru(HEDTA)NO] also inhibited the carrageenin-induced mechanical hyperalgesia and increase of myeloperoxidase activity in paw skin samples. Mechanistically, [Ru(HEDTA)NO] inhibited carrageenin-induced production of the hyperalgesic cytokines tumor necrosis factor-α and interleukin-1ß, and decrease of reduced glutathione levels. Furthermore, the inhibitory effect of [Ru(HEDTA)NO] in the carrageenin-induced hyperalgesia and myeloperoxidase activity was prevented by the treatment with ODQ (soluble guanylyl cyclase inhibitor), KT5823 (protein kinase G inhibitor) and glybenclamide (ATP-sensitive potassium channel inhibitor), indicating that [Ru(HEDTA)NO] inhibits inflammatory hyperalgesia by activating the cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that [Ru(HEDTA)NO] exerts its analgesic effect in inflammation by inhibiting pro-nociceptive cytokine production, oxidative imbalance and activation of the nitric oxide/cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway in mice.

The ruthenium NO donor, [Ru(bpy)2(NO)SO3](PF6), inhibits inflammatory pain: involvement of TRPV1 and cGMP/PKG/ATP-sensitive potassium channel signaling pathway.

The activation of nitric oxide (NO) production is an analgesic mechanism shared by drugs such as morphine and diclofenac. Therefore, the controlled release of low amounts of NO seems to be a promising analgesic approach. In the present study, the antinociceptive effect of the ruthenium NO donor [Ru(bpy)2(NO)SO3](PF6) (complex I) was investigated. It was observed that complex I inhibited in a dose (0.3-10mg/kg)-dependent manner the acetic acid-induced writhing response. At the dose of 1mg/kg, complex I inhibited the phenyl-p-benzoquinone-induced writhing response and formalin- and complete Freund's adjuvant-induced licking and flinch responses. Additionally, complex I also inhibited transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent overt pain-like behavior induced by capsaicin. Complex I also inhibited the carrageenin-induced mechanical hyperalgesia and increase of myeloperoxidase activity (MPO) in paw skin samples. The inhibitory effect of complex I in the carrageenin-induced hyperalgesia, MPO activity and formalin was prevented by the treatment with ODQ, KT5823 and glybenclamide, indicating that complex I inhibits inflammatory hyperalgesia by activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. The present study demonstrates the efficacy of a novel ruthenium NO donor and its analgesic mechanisms.